The mTOR Deficiency in Monocytic Myeloid-Derived Suppressor Cells Protects Mouse Cardiac Allografts by Inducing Allograft Tolerance.

Jiawei Li,Yi Zhang,Jingjing Liu,Chao Zhang,Tongyu Zhu,Renyan Wu,Tianying Yang,Yue Qiu,Juntao Chen,Mingnan Zhang,Ruiming Rong

doi:10.3389/fimmu.2021.661338

Abstract

BackgroundMyeloid-derived suppressor cells (MDSCs) can prevent allograft rejection and induce immune tolerance in transplantation models. Previous studies have demonstrated that inhibition of mTOR signaling can enhance the MDSC protective effect in heart transplantation (HTx) by promoting MDSC expansion. In addition, mTOR inhibition is related to autophagy. The present study investigated the protective mechanism of mTOR-deficient monocytic MDSCs (M-MDSCs) in mouse HTx.MethodsMyeloid-specific mTOR conditional knockout mice were generated to obtain mTOR−/− M-MDSCs. The proliferation and immunosuppressive function of mTOR−/− M-MDSCs were determined by flow cytometry and T cell proliferation assays. The mTOR−/− M-MDSC intracellular autophagy levels were determined using western blotting and electron microscopy. RNAseq analysis was performed for wild-type (WT) and mTOR−/− M-MDSCs. Allogeneic HTx mouse model was established and treated with WT or mTOR−/− M-MDSCs. Enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry assays were performed to determine WT and mTOR−/− M-MDSC-induced immune tolerance.ResultsThe mTOR deficiency promoted M-MDSC differentiation and enhanced intracellular autophagy levels in vivo and in vitro. mTOR deficiency also enhanced the immunosuppressive function of M-MDSCs. In addition, infusing with WT and mTOR−/− M-MDSCs prolonged cardiac allograft survival and established immune tolerance in recipient mice by inhibiting T cell activation and inducing regulatory T cells.ConclusionmTOR deficiency enhances the immunosuppressive function of M-MDSCs and prolongs mouse cardiac allograft survival.

Highlights

Myeloid-derived suppressor cells (MDSCs) were first discovered in tumorigenesis, but were later found to be involved in other pathological conditions, such as obesity, sepsis, and organ transplantation [1]
The mammalian target of rapamycin (mTOR) deficiency promoted monocytic MDSCs (M-MDSCs) differentiation and enhanced intracellular autophagy levels in vivo and in vitro. mTOR deficiency enhanced the immunosuppressive function of M-MDSCs
The present study found that mTOR deficiency can promote M-MDSC differentiation and enhance intracellular autophagy levels, which leads to the upregulated immunosuppressive function of M-MDSCs

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) were first discovered in tumorigenesis, but were later found to be involved in other pathological conditions, such as obesity, sepsis, and organ transplantation [1]. MDSCs are heterogeneous progenitor and immature myeloid cells. In TME, MDSCs suppress T cell activation, regulate inflammatory cytokines, and promote immune tolerance to enhance tumor growth [5]. The function of T cell inhibition by MDSCs is correlated with the induction and recruitment of regulatory T cells (Tregs) [2, 6, 7]. Myeloid-derived suppressor cells (MDSCs) can prevent allograft rejection and induce immune tolerance in transplantation models. Previous studies have demonstrated that inhibition of mTOR signaling can enhance the MDSC protective effect in heart transplantation (HTx) by promoting MDSC expansion. The present study investigated the protective mechanism of mTOR-deficient monocytic MDSCs (M-MDSCs) in mouse HTx

Methods

Results

Conclusion